Study shows how neural networks adapt to the presence of a toxic HIV protein.

The incidence of HIV-associated dementia has declined dramatically since the introduction of potent combined antiretroviral therapy; however, milder forms of HIV-associated neurocognitive disorders (HAND) persist. Some 30 to 50 % of HIV-infected individuals have HAND. With an increasing proportion of HIV-infected individuals at risk of HAND, the development of a treatment and mapping of pathology is critical. Now, a study from researchers at the University of Minnesota shows that the HIV protein transactivator of transcription (Tat) alters the activity of networked neurons and that the network adapted to the presence of the toxin. The team state that Tat alters the excitability of networked neurons by a process that requires binding to cell surface proteins, and the activity of the networked neurons adapted in the sustained presence of the HIV protein. The study is published in the journal Current HIV Research.

Previous studies show the HIV-1 transactivator of transcription (Tat) protein is released by infected cells and contributes to the pathogenesis of HAND, however, many of the underlying mechanisms remain poorly understood. Also, infection with HIV is associated with increased incidence of new-onset seizures in a significant percentage of patients, once again the specific cause of seizure disorders remains unknown. The current study work establishes the principle that networks of neurons adapt to the presence of a toxic HIV protein and suggest that viewing EEG changes as an adaptive response might facilitate therapeutic intervention.

The current study used calcium imaging and whole-cell patch-clamp recording to study the effects of Tat on the spontaneous synaptic activity in rat hippocampal neurons in culture. Results show that Tat triggered aberrant network activity that exhibited a decrease in the frequency of spontaneous action potential bursts and Ca²⁺ spikes with a simultaneous increase in burst duration and Ca²⁺ spike amplitude.

Data findings show that network changes were apparent after 4 h treatment with Tat and required the low-density lipoprotein receptor-related protein (LRP). Results show that the activity returned to control levels in the maintained presence of Tat for 24 h. The group state that these observations indicate that Tat causes aberrant network activity, which is dependent on LRP, and adapts following prolonged exposure. They go on to add that changes in network excitability may contribute to Tat-induced neurotoxicity in vitro and seizure disorders in vivo.

The team surmise that their findings suggest that adaptation of neural networks may be a neuroprotective response to the sustained presence of the neurotoxic protein Tat and could underlie the behavioural and electrophysiological changes observed in HAND. For the future, the researchers state that their studies will focus on the mechanism underlying changes in network function to identify new targets for the treatment of neurological disorders in HIV+ patients.

Source: Bentham Science Publishers

Neural networks adapt to the presence of a toxic HIV protein - neuroinnovations

Michelle Petersen

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